1. Field of the Invention
The present invention concerns a biodegradable vaginal barrier device. More particularly, the present invention concerns a bio-erodible microbicidal vaginal sponge made from hydroxypropylmethylcellulose phthalate and/or cellulose acetate phthalate.
2. Background Information
Applicants have previously reported that cellulose acetate phthalate (xe2x80x9cCAPxe2x80x9d) and hydroxypropylmethylcellulose phthalate (xe2x80x9cHPMCPxe2x80x9d) prevent infection by the human immunodeficiency virus type 1 (HIV-1). Additional studies showed that CAP also blocked infection by several herpesviruses (Neurath, A. R., Strick, N., Li, Y. -Y., Jiang, S., xe2x80x9cDesign of a xe2x80x98Microbicidexe2x80x99 for Prevention of Sexually Transmitted Diseases Using xe2x80x98Inactivexe2x80x99 Pharmaceutical Excipientsxe2x80x9d, Biologicals, 27, 11-21, (1999); U.S. Pat. No. 5,985,313; U.S. Pat. No. 6,165,493). CAP formulated into creams was shown to inactivate HIV-1, several herpesviruses as well as nonviral sexually transmitted disease (STD) pathogens (Neurath, A. R., Strick, N., Li, Y. -Y., Jiang, S., xe2x80x9cDesign of a xe2x80x98Microbicidexe2x80x99 for Prevention of Sexually Transmitted Diseases Using xe2x80x98Inactivexe2x80x99 Pharmaceutical Excipientsxe2x80x9d, Biologicals, 27, 11-21, (1999); U.S. Pat. No. 5,985,313). The formulated CAP also inactivated bacteria associated with bacterial vaginosis (Neurath, A. R., Li, Y. -Y., Mandeville R., Richard, L., xe2x80x9cIn vitro Activity of a Cellulose Acetate Phthalate Topical Cream Against Organisms Associated with Bacterial Vaginosisxe2x80x9d, J. Antimicrob. Chemother., 45, 713-714). Results of experiments in animal models indicated that CAP formulations prevented vaginal infections by the simian immunodeficiency virus (SIV) of macaques and by herpesvirus type 2 (HSV-2) of mice (In press: Manson, K. H., Wyand, M. S., Miller, C., Neurath, A. R., xe2x80x9cThe Effects of a Cellulose Acetate Phthalate Topical Cream on Vaginal Transmission of SIV in Rhesus Monkeysxe2x80x9d, Antimicrobial Agents and Chemotherapy; Guotoku, T., Aurelian, L., Neurath, A. R., xe2x80x9cCellulose Acetate Phthalate (CAP): An xe2x80x98Inactivexe2x80x99 Pharmaceutical Excipient With Antiviral Activity in the Mouse Model of Genital Herpesvirus Infectionxe2x80x9d, Antiviral Chemistry and Chemotherapy, 10, 327-332). Cumulatively these results indicate that formulations of CAP represent preferred microbicides for prevention of sexual transmission of a variety of STD pathogens.
To minimize the probability of conception, as well as of sexual transmission of HIV-1 and other STD pathogens, it appears critical to combine chemical and mechanical barriers (Shihata, A., xe2x80x9cThe Clinical Application of Basic Anatomy and Physiology in Microbicide Developmentxe2x80x9d, Microbicides 2000, Mar. 13-16, 2000, p. 29). The combinations of mechanical and chemical barriers in use at this time are based on solid mechanical devices combined with added detergents, Nonoxynol-9 (xe2x80x9cN-9xe2x80x9d) and other ingredients. Examples of such devices are as follows: Protectaid(trademark) sponge (Axcan Ltd.), the Today Sponge(trademark) (Allendale Pharmaceuticals, Inc., Allendale, N.J.) and the FemCapT(trademark) (Shihata, A. A., xe2x80x9cThe FemCap: A New Contraceptive Choicexe2x80x9d, Eur. J. Contracept. Reprod. Health Care, 3(3), pp. 160-166, (1998)). The disadvantage of these devices is that they have to be removed after use and either discarded (sponges), contributing to waste disposal problems, or cleaned for reuse (FemCap(trademark)), an impractical alternative for developing countries with scarce clean water supplies. Another disadvantage of these devices is the use of N-9 as a chemical barrier, since N-9 has been shown recently to increase the risk of sexual transmission of HIV-1 instead of blocking it. For all these reasons, alternative devices without these disadvantages are needed.
To avoid one of the above problems, such as the necessity to remove the device after use, a bio-erodible contraceptive suppository also expected to have microbicidal properties, has been described by Britton, P. et al. (U.S. Pat. No. 5,863,553). The Britton et al. device disperses or dissolves after use and therefore does not need to be removed. However the Britton et al. device still has the following disadvantages: (1) it uses N-9 as an added ingredient to provide contraceptive or microbicidal activity and (2) the device uses gelatine as a major ingredient to assure mechanical stability and ease of insertion. Gelatine is generally an undesirable animal derived product, which may potentially transmit spongiform encephalopathies (i.e., mad cow disease, Creuzfeldt-Jakob-Disease). For this reason, gelatine derived from animals susceptible to spongiform encephalopathies is not recommended, if avoidable, for medicinal use.
Devices with built-in contraceptive and microbicidal activity were disclosed by T. H. Barrows in U.S. Pat. No. 4,360,013. The Barrows devices are based on acidic polymers providing a low pH expected to be lethal to viruses, microorganisms and semen. However one of the proposed materials, oxidized cellulose (Oxycel) is prohibitively expensive and is not rapidly biodegradable. The general disadvantage of the acidic polymers listed in U.S. Pat. No. 4,360,013 is that the acidic functionalities would be neutralized in the presence of semen/seminal fluid. The neutralized polymers lack antiviral or antimicrobial activity.
It is an object of the present invention to provide a biodegradable microbicidal vaginal barrier device.
It is a further object of the present invention to furnish a bio-erodible microbicidal device for the prevention of sexually transmitted diseases.
It is a still further object of the present invention to provide a biodegradable vaginal sponge with built-in microbicidal activity.
The present invention satisfies the above objects and provides further objects, aims and advantages.
The present invention thus concerns an intravaginal bio-erodible-microbicidal barrier device comprising:
(a) at least one micronized compound selected from the group consisting of cellulose acetate phthalate and hydroxyoropylmethylcellulose phthalate, and
(b) at least one water soluble or water dispersible cellulose compound selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose and hydroxypropylethylcellulose.
The cellulose acetate phthalate can be contained in an xe2x80x9cAQUATERICxe2x80x9d composition which also contains poloxamers and aceylated monoglycerides.
The present invention also relates to a method of making an intravaginal bio-erodible microbicidal barrier device comprising:
(a) providing at least one micronized compound selected from the group consisting of cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate;
(b) adding to the at least one micronized compound, an aqueous solution of at least one water soluble or water dispersible cellulose compound selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose and hydroxypropylethylcellulose, to form a suspension;
(c) foaming the suspension from step (b) to form a foam;
(d) disposing the foam from step (c) into a mold and freezing the foam to form a frozen foam; and
(e) freeze-drying the frozen foam from step (d) to remove water.
The present invention also is directed to another method of making an intravaginal bio-erodible microbicidal barrier device comprising:
(a) preparing a first solution and a second solution, the first solution comprising at least one water soluble or water dispersible cellulose compound selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose and hydroxypropylethylcellulose, suspended or dissolved in water; the second solution comprising at least one compound selected from the group consisting of cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, dissolved in at least one organic solvent;
(b) combining the first solution and the second solution to result in an emulsion in which the cellulose acetate phthalate or the hydroxypropylmethylcellulose phthalate is in a micronized form;
(c) foaming the emulsion from step (b) to form a foam;
(d) disposing the foam from step (c) into a mold and freezing the foam to form a frozen foam; and
(e) freeze-drying the frozen foam from step (d) to remove water and to remove the organic solvent.
The other ingredients in the xe2x80x9cAQUATERICxe2x80x9d composition such as poloxamers and aceylated monoglycerides are not needed to prepare the sponge according to the preceding method.